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Table 3. The structures and biological activities of the designed new compounds
Compound
R1
R2
X
na
MaxÁFRPb
MaxÁHRc
MaxÁFCd
Dofetilide
VIa
VIb
VIc
VId
VIe
VIf
VIg
VIh
-CH3
-CH3
-CH2C6H5
-COCH3
-CH2CHCH2
-CH2CHCH2
-COC6H5
-CH2C6H5
-COCH3
-H
-H
-H
-H
-NHSO2CH3-4
5
3
3
3
2
2
2
2
2
2
24.02
20.2
Ne
58.36
9.77
Ne
5.33
Ne
Ne
30.03
28.51
31.8
46.17
15.18
8.33
17.05
20.25
25
37.87
16.67
16.67
33.33
25
Ne
Ne
-X
-X
-X
-X
-X
-X
-X
-X
-X
-H
-SO2CH3
-H
-SO2CH3
-SO2CH3
-SO2CH3
20
17.86
20.51
20.69
VIi
-CH3
12.02
an=the sample number.
bMaxÁFRP=the maximal percent change of delaying FRP in mM (%).
cMaxÁHR=the maximal percent change of heart rate in mM (%).
dMaxÁFC=the maximal percent change of force of constriction in mM (%).
eN=No eect in mM.
New analogues design, synthesis and bioassay. Accord-
ing to CoMFA and CoMSIA analyses (Fig. 2), we can
see that adding bulky and hydrophobic groups to the
phenyl moiety of phenoxyethane of dofetilide may
increase the bioactivity. Following this clue, we designed
nine new analogues (compounds VIa i, Table 3). Scheme 1
depicts the synthetic sequence of these compounds.
Compound I was substituted by using p-nitrophenethyl-
amine hydrobromide (II), giving the key intermediates
III. N-Methylation was performed with satisfactory
yields in formate with formaldehyde, giving compound
IVa. The analogues were prepared as described in step b.
N-Alkylation of compound III with benzyl chloride, p-
chlorobenzyl chloride, allyl bromide, benzoyl chloride
and acetic anhydride was conducted by re¯uxing with
Conclusion
In summary, 3D-QSAR analyses have been performed
on 17 methylsulfonamido phenylethylamine analogues6,7
by use of CoMFA and CoMSIA methods. The 3D-
QSAR models proved
a good predictive ability.
According to the clues provided by 3D-QSAR analyses,
we designed and synthesized a series of new analogues
of methanesulfonamido phenylethylamine (VIa i). Phar-
macological assay indicated that the eective concentra-
tions of delaying FRP 10 ms of these new compounds
have a good correlation to the 3D-QSAR predicted
data. It is remarkable that the maximal percent change
of delaying FRP in mM of compound VIc is much
higher than that of dofetilide, but it reduced cardiac
muscle constriction, which may be due to blocking of
complex K+/Ca2+ channel. The results showed that
experimental data correlates well with predicted activity,
indicating that the 3D-QSAR models are reliable.
K2CO3 in acetone and aorded compounds IVb i
,
respectively, which were then reduced with Fe in hydro-
chloric acid. Finally, the analogues of general structure
VI were furnished by methylsulfonation with triethyl-
amine. Compounds of this class are thermally unstable
and should be handled in an ice bath.
Acknowledgements
With completion of the synthesis, the in vitro K+
channel inhibitory activity of these nine target com-
pounds as compared with dofetilide was measured.
According to the method of Wettwer et al.,13 the eec-
tive concentrations of nine methanesulfonamido phenyl-
ethylamine analogues upon increasing FRP in isolated
animal atrium were evaluated utilizing a pair-electric
stimulus technique. The results are summarized in Table 3.
It showed that compound VIa prolonged FRP, reduced
heart rate and strengthened cardiac muscle constriction.
The level of prolonging FRP is equivalent to that of
dofetilide in mM, MaxÁFRP=24.02%. It is remarkable
that the maximal percent change of delaying FRP in
mM of compound VIc is 58%, which is higher than that
of dofetilide (Table 3), but it reduced cardiac muscle
constriction, which may be due to blocking of complex
K+/Ca2+ channel. Further investigations are currently
in progress.
The authors gratefully acknowledge Dr. Xuntian Jiang,
Dr. Dongxiang Liu, Dr. Xiaojian Tan and Dr. Feng
Cheng for enthusiastic help.
References and Notes
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